COVID-19-associated-mucormycosis: possible role of free iron uptake and immunosuppression

Abstract

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.

Keywords: COVID-19; Free iron; Hyperferritinemia; Mucormycosis; Pathogenesis; Rhizopus oryzae.

Fig. 1

Different mechanisms utilized by Mucorales to obtain iron from the host. High-affinity iron permeases on the cytoplasmic membrane can convert the less soluble ferric ion into more soluble ferrous ions, followed by their internalization through the copper oxidase-iron permease (FTR1) complex. The complex oxidizes the ferrous form into the ferric form required to properly utilize the ion in intracellular processes. A xenosiderophore, Deferoxamine, may strip Fe³⁺ ion from host transferrin and produce ferrioxamine (Deferoxamine-Fe³⁺ complex) that is reduced into ferrous ion and internalized by FTR1 complex. Other endogenous siderophores are synthesized by the fungus chelate iron extracellularly, and the whole complex may be internalized through a shuttle mechanism. Alternatively, the siderophore-iron complexes may be reduced through membrane permeases to generate Fe²⁺ ions, followed by internalization by the FTR1 complex. The angioinvasive nature of the infection also reveals that heme can be a potential source of iron. The heme-Fe³⁺ complex may be entirely internalized and then acted on by the heme oxygenases intracellularly or reduced on the surface to generate Fe²⁺ ions to be taken in by the FTR1 complex. Overexpression of the FTR1 gene during infection correlates to the requirement of this complex in internalizing all the extracellular ferrous ions and some iron chelator complexes

Fig. 2

Higher levels of free iron accumulation during COVID-19 infection. The SARS-CoV-2 virus displays hyperferritinemic syndrome (hyperferritinemia and hyperinflammation). The viral infection activates macrophages, which stimulates the release of elevated cytokine content and serum ferritin. Serum ferritin is advantageous to block secondary fungal infection as it sequesters free iron, resulting in iron starvation for Mucorales. During iron overload, like hyperferritinemia generated in COVID-19 infection, serum ferritin stored in hepatocyte undergoes denaturation in the lysosome, and the Fe²⁺ bound to ferritin is released. The labile Fe²⁺ reacts with hydrogen peroxide (H₂O₂) to generate highly toxic reactive oxygen species (ROS) or lipid peroxides to generate lipid radicals, which induces hepatic cell death and releases the stored labile iron and serum ferritin extracellularly. Moreover, the SARS-CoV-2 virus may attack hemoglobin or induce hepcidin dysregulation, the host's major iron homeostasis regulation hormone. All of these marks free iron availability for fungal acquisition, facilitating mucormycosis in COVID-19 patients